Stroke is a leading cause of disability in the US. Predictors of poor functional recovery post-stroke include impairments in cognition and motivation. Recent evidence indicates that acetylcholinesterase inhibitors may improve cognition and motivation; hence, their use post-stroke may lead to improved rehabilitation outcomes. We have demonstrated that the use of the acetylcholinesterase inhibitor, donepezil is associated with improved functional recovery in a pilot sample (n = 40) of elderly, cognitively impaired stroke survivors undergoing inpatient rehabilitation. Specifically, in this 12 week open-label study, those subjects receiving donepezil experienced a clinically meaningful 14 point greater improvement on the Functional Independence Measure (FIM) than an archival comparator group. We propose a 12-week double-blind randomized clinical trial (RCT) of donepezil in older cognitively impaired ischemic stroke survivors who are actively undergoing rehabilitation. We will randomize 200 subjects, aged 50 years and older, to donepezil (titrated to 10mg/d) or placebo. The primary goal is to evaluate the utility of donepezil in promoting functional recovery. We hypothesize that subjects randomized to donepezil will have superior performance on the FIM over the12 week study compared to those who received placebo. We will re- assess subjects (off study medication) at 18 and 24 weeks post randomization to assess the durability of donepezil's pro-recovery effect. We will assess efficacy via an intent-to-treat repeated measures analyses using mixed models. Secondary goals include (1) to examine donepezil's effect on cognition and apathy and (2) to explore patient characteristics that are associated with variability of the drug's impact on functional recovery (FIM) as well as the relationship between the outcomes of function recovery, cognition, apathy. This proposed study is led by a new principal investigator and integrates an interdisciplinary team of investigators with a track record of studies relevant to stroke rehabilitation and the neuropsychiatric outcomes of cerebrovascular disease. The aims of this proposed study are in line with the NCMRR's research priorities, namely [to] conduct controlled clinical trials to establish&efficacy of treatments to reduce impairments, functional limitations, and disabilities and [to] identify factors that may modify the relationships among & impairments, functional limitations, [and] disabilities' (NIH Publication 93-3509 and Report to NACHHD Council January 2006). Improving rehabilitation outcomes after stroke is highly PUBLIC HEALTH RELEVANCE: Stroke is currently one of the main causes of long-term disability in the US. The total number of stroke survivors, currently estimated as 5.5 million Americans, will continue to increase as the population ages and as the management of acute stroke continues to improve survival. This study holds promise to identify a pharmacologic intervention, which when combined with rehabilitation, would be a simple and widely generalizable strategy to promote post-stroke functional recovery.